tbuckley/cabot-search huggingface dataset:
Spirometric patterns in young and middle-aged adults: a 20-year European study
Authors: Anne-Elie Carsin, Judith Garcia-Aymerich, Simone Accordini, Shyamali Dharmage, Bénédicte Leynaert, Marti de las Heras, Lidia Casas, Seraina Caviezel, Pascal Demoly, Bertil Forsberg, Thorarinn Gislason, Angelo Guido Corsico, Christer Janson, Rain Jogi, Jesús Martínez-Moratalla, Dennis Nowak, Leopoldo Palacios Gómez, Isabelle Pin, Nicole Probst-Hensch, Chantal Raherison-Semjen, Giulia Squillacioti, Cecilie Svanes, Kjell Torén, Isabel Urrutia, Ismael Huerta, Josep Maria Anto, Debbie Jarvis, Stefano Guerra
Journal: Thorax (2023)

Background Understanding the natural history of abnormal spirometric patterns at different stages of life is critical to identify and optimise preventive strategies. We aimed to describe characteristics and risk factors of restrictive and obstructive spirometric patterns occurring before 40 years (young onset) and between 40 and 61 years (mid-adult onset). Methods We used data from the population-based cohort of the European Community Respiratory Health Survey (ECRHS). Prebronchodilator forced expiratory volume in one second (FEV 1 ) and forced vital capacity (FVC) were assessed longitudinally at baseline (ECRHS1, 1993–1994) and again 20 years later (ECRHS3, 2010–2013). Spirometry patterns were defined as: restrictive if FEV 1 /FVC≥LLN and FVC&lt;10th percentile, obstructive if FEV 1 /FVC&lt;LLN or normal otherwise. Five spirometry patterns were derived depending on whether participants never developed restrictive/obstructive (normal), developed restrictive/obstructive at baseline (young onset) or at last follow-up (mid-adult onset). The characteristics and risk factors associated with these patterns were described and assessed using multilevel multinomial logistic regression analysis adjusting for age, sex, sample (random or symptomatic) and centre. Results Among 3502 participants (mean age=30.4 (SD 5.4) at ECRHS1, 50.4 (SD 5.4) at ECRHS3), 2293 (65%) had a normal, 371 (11%) a young restrictive, 301 (9%) a young obstructive, 187 (5%) a mid-adult onset restrictive and 350 (10%) a mid-adult onset obstructive spirometric pattern. Being lean/underweight in childhood and young adult life was associated with the occurrence of the young spirometric restrictive pattern (relative risk ratio (RRR)=1.61 95% CI=1.21 to 2.14, and RRR=2.43 95% CI=1.80 to 3.29; respectively), so were respiratory infections before 5 years (RRR=1.48, 95% CI=1.05 to 2.08). The main determinants for young obstructive, mid-adult restrictive and mid-adult obstructive patterns were asthma, obesity and smoking, respectively. Conclusion Spirometric patterns with onset in young and mid-adult life were associated with distinct characteristics and risk factors.
Future-case control crossover analysis for adjusting bias in case crossover studies
Authors: Wei-Ching Huang, Edward Chia-Cheng Lai
Journal: BMJ (2023)

This article outlines the issues of exposure time trends in the case crossover design and the implementation of the case-case-time-control design, a control crossover analysis using “future cases” to adjust the exposure time trends. The future-case control crossover analysis minimises the influence of constant time confounders, as well as the protopathic bias arising from exposure time trends.
Determination of the most appropriate ACR response definition for contemporary drug approval trials in rheumatoid arthritis
Authors: Victoria Konzett, Andreas Kerschbaumer, Josef S Smolen, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2023)

Objectives To evaluate which American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) should primarily be used for efficacy claims in future drug approval trials of rheumatoid arthritis (RA). Methods We systematically searched EMBASE, Medline and the Cochrane Library for randomised controlled RA drug approval trials of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). We included full-text articles reporting ACR response rates for multiple time points over a 24-week placebo-controlled period and visualised normalised response trajectories over time in different patient populations. Using mixed-effect logistic regression, we calculated the proportion of ACR responders per outcome and time point, and compared the discriminant validity of these metrics at multiple time points. Results We screened 12 680 records and included 45 in the final analysis. Discriminative capacity of the ACR20 was high across all time points, whereas ACR50 and ACR70 showed highest discrimination towards the end of the placebo-controlled periods. This effect could be observed in all patient populations and compound groups. Faster response to treatment was observed in DMARD naïve patient populations when compared with DMARD insufficient responders. Conclusion ACR20 remains the most powerful discriminator between active treatment and placebo, especially when early discrimination is of primary interest. At the same time, our results support the selection of more stringent thresholds if later time points shall be evaluated, given their comparable discriminant but higher clinical face validity.
Barriers and enablers influencing female athlete return-to-sport postpartum: a scoping review
Authors: Boden Joel Tighe, Susan L Williams, Courtney Porter, Melanie Hayman
Journal: British Journal of Sports Medicine (2023)

Objective Motherhood within sport has become more common with many female athletes seeking to return-to-sport (RTS) postpartum; yet few sport organisations possess policies that support female athletes to RTS postpartum. Our aim was to synthesise existing literature to identify the barriers and enablers that influence female athlete RTS postpartum to help guide the development of evidence-based policies to support postpartum athlete RTS. Design Scoping review. Data sources Ovid-Medline, Embase, SportDiscus and Scopus were systematically searched. Reference lists of eligible studies were also searched to identify additional studies of relevance. Eligibility criteria Original, empirical, peer-reviewed, English-language studies reporting on female athletes and their RTS postpartum. Reviews, book chapters and grey literature were excluded. Results Twenty-two studies were included in this review. Identified barriers and enablers reflected 11 categories which occurred within and/or across three domains of the socioecological model. Five key factors were found to significantly influence female athlete RTS postpartum including (1) postpartum recovery time; (2) time to manage motherhood and sport demands; (3) sport organisation policies; (4) stereotypes; and (5) social support. Conclusion Various barriers and enablers exist that influence successful RTS postpartum. These factors present opportunities for clinicians and sport organisations to improve their support of postpartum athletes. Paid maternity leave, offering job security, travel support for carer and child and affordable and accessible childcare are critical policy inclusions to appropriately support female athletes in their RTS postpartum.
Association between recently raised anticholinergic burden and risk of acute cardiovascular events: nationwide case-case-time-control study
Authors: Wei-Ching Huang, Avery Shuei-He Yang, Daniel Hsiang-Te Tsai, Shih-Chieh Shao, Swu-Jane Lin, Edward Chia-Cheng Lai
Journal: BMJ (2023)

To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults.Case-case-time-control study (ie, incorporating a case crossover design and a control crossover design consisting of future cases).Taiwan's National Health Insurance Research Database.317 446 adults aged ≥65 who were admitted to hospital because of an incident acute cardiovascular event between 2011 and 2018. Acute cardiovascular events included myocardial infarction, strokes, arrhythmias, conduction disorders, and cardiovascular death.The anticholinergic burden was measured for each participant by adding up the anticholinergic scores for individual drugs using the Anticholinergic Cognitive Burden Scale. Scores were classified into three levels (0 points, 1-2 points, and ≥3 points). For each participant, anticholinergic burden levels during hazard periods (day -1 to -30 before the cardiovascular event) were compared with randomly selected 30 day reference periods (ie, periods between days -61 and -180). Conditional logistic regression determined odds ratios with 95% confidence intervals to evaluate the association between acute cardiovascular events and recently raised anticholinergic burden.The crossover analyses included 248 579 current cases. Participants' average age on the index date was 78.4 years (standard deviation 0.01), and 53.4% were men. The most frequently prescribed drugs with anticholinergic activity were antihistamines (68.9%), gastrointestinal antispasmodics (40.9%), and diuretics (33.8%). Among patients with varying levels of anticholinergic burden in different periods, more patients carried higher levels of anticholinergic burden during hazard periods than during reference periods. For example, 17 603 current cases had 1-2 points of anticholinergic burden in the hazard period with 0 points in the reference period, while 8507 current cases had 0 points in the hazard period and 1-2 points in the reference period. In the comparison of 1-2 points versus 0 points of anticholinergic burden, the odds ratio was 1.86 (95% confidence interval 1.83 to 1.90) in the case crossover analysis and 1.35 (1.33 to 1.38) in the control crossover analysis, which yielded a case-case-time-control odds ratio of 1.38 (1.34 to 1.42). Similar results were found in the comparison of ≥3 versus 0 points (2.03, 1.98 to 2.09) and ≥3 versus 1-2 points (1.48, 1.44 to 1.52). The findings remained consistent throughout a series of sensitivity analyses (eg, cut-off points for anticholinergic burden categories were redefined and different scales were used to measure anticholinergic burden).An association was found between recently raised anticholinergic burden and increased risk of acute cardiovascular events. Furthermore, a greater increase in anticholinergic burden was associated with a higher risk of acute cardiovascular events.
A novel multi-ancestry proteome-wide Mendelian randomization study implicates extracellular proteins, tubular cells, and fibroblasts in estimated glomerular filtration rate regulation
Authors: Matthew B. Lanktree, Nicolas Perrot, Andrew Smyth, Michael Chong, Sukrit Narula, Meera Shanmuganathan, Zachary Kroezen, Philip Britz-Mckibbin, Mario Berger, Joan C. Krepinsky, Marie Pigeyre, Salim Yusuf, Guillaume Paré
Journal: Kidney International (2023)

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study. Using two-sample Mendelian randomization, individual variants' effects on biomarker concentration were correlated with their effects on eGFR and kidney traits from published genome-wide association studies (GWAS). Genetically altered concentrations of 22 biomarkers were associated with eGFR above a Bonferroni-corrected significance threshold. Five biomarkers were previously identified by GWAS (UMOD, FGF5, LGALS7, NINJ1, COL18A1). Nine biomarkers were within 1 Mb of the lead GWAS variant but the gene for the biomarker was unidentified as the candidate for the GWAS signal (INHBC, TNFRSF11A, TCN2, PXN1, PRTN3, PSMD9, TFPI, ITGB6, CA3). Single-cell transcriptomic data indicated the 22 biomarkers are expressed in kidney tubules, collecting duct, fibroblasts, and immune cells. Pathway analysis showed significant enrichment of identified biomarkers in the extracellular kidney parenchyma. Thus, using genetic regulators of biomarker concentration via proteome-wide Mendelian randomization, we identified 22 biomarkers that appear to causally impact eGFR in either a beneficial or adverse manner. The current study provides rationale for novel therapeutic targets for eGFR and emphasized a role for extracellular proteins produced by tubular cells and fibroblasts for impacting eGFR.
Developing the West African Digital Mental Health Alliance (WADMA)
Authors: Lola Kola, Anna Larsen, Seth Asafo, Dzifa Abra Attah, Alexa Beaulieu, Jonathan Kuma Gavi, Kevin Hallgren, Arya Kadakia, Kwadwo Obeng, Sammy Ohene, Jaime Snyder, Angela Ofori-Atta, Dror Ben-Zeev
Journal: Nature Medicine (2023)
Second-site suppressor mutations reveal connection between the drug-binding pocket and nucleotide-binding domain 1 of human P-glycoprotein (ABCB1)
Authors: Megumi Murakami, Andaleeb Sajid, Sabrina Lusvarghi, Stewart R. Durell, Biebele Abel, Shahrooz Vahedi, John Golin, Suresh V. Ambudkar
Journal: Drug Resistance Updates (2023)
Blocking Tim-3 enhances the anti-tumor immunity of STING agonist ADU-S100 by unleashing CD4<sup>+</sup> T cells through regulating type 2 conventional dendritic cells
Authors: Jing Luo, Shuju Pang, Zhenzhen Hui, Hua Zhao, Shilei Xu, Wenwen Yu, Lili Yang, Qian Sun, Xishan Hao, Feng Wei, Jian Wang, Xiubao Ren
Journal: Theranostics (2023)

Rationale: An immunosuppressive tumor microenvironment (TME) is a major obstacle in tumor immunotherapy. Stimulator of interferon genes (STING) agonists trigger an inflammatory innate immune response to potentially overcome tumor immunosuppression. While STING agonists may hold promise as potential cancer therapy agents, tumor resistance to STING monotherapy has emerged in clinical trials, and the mechanisms remain unclear. Methods: The in vivo anti-tumor immunity of STING agonist ADU-S100 (S100), plus anti-T cell immunoglobulin and mucin-domain containing-3 antibody (αTim-3) were measured using murine tumor models. Tumor-specific T cell activation and alterations in the TME were detected using flow cytometry. The maturation and function of dendritic cells (DC) were also measured using flow cytometry, and the importance of CD4+ T cells in combination therapy was measured by blocking antibodies. Additionally, the effect of S100 on CD4+ T was verified via in vitro assays. Lastly, the impact of conventional dendritic cells (cDC) 2 with a high expression of Tim-3 on survival or therapeutic outcomes was further evaluated in human tumor samples. Results: S100 boosted CD8+ T by activating cDC1 but failed to initiate cDC2. Mechanistically, the administration of S100 results in an upregulation of Tim-3 expressed in cDC2 (Tim-3+cDC2) in both mice and humans, which is immunosuppressive. Tim-3+cDC2 restrained CD4+ T and attenuated the CD4+ T-driven anti-tumor response. Combining S100 with αTim-3 effectively promoted cDC2 maturation and antigen presentation, releasing CD4+ T cells, thus reducing tumor burden while prolonging survival. Furthermore, high percentages of Tim-3+cDC2 in the human TME predicted poor prognosis, whereas the abundance of Tim-3+cDC2 may act as a biomarker for CD4+ T quality and a contributing indicator for responsiveness to immunotherapy. Conclusion: This research demonstrated that blocking Tim-3 could enhance the anti-tumor immunity of STING agonist ADU-S100 by releasing CD4+ T cells through regulating cDC2. It also revealed an intrinsic barrier to ADU-S100 monotherapy, besides providing a combinatorial strategy for overcoming immunosuppression in tumors.
Phase I clinical evaluation of <sup>99m</sup>Tc-labeled Affibody molecule for imaging HER2 expression in breast cancer
Authors: Olga Bragina, Vladimir Chernov, Mariia Larkina, Anstasiya Rybina, Roman Zelchan, Eugeniy Garbukov, Maryam Oroujeni, Annika Loftenius, Anna Orlova, Jens Sörensen, Fredrik Y. Frejd, Vladimir Tolmachev
Journal: Theranostics (2023)

The determination of tumor human epidermal growth factor receptor type 2 (HER2) status is of increasing importance with the recent approval of more efficacious HER2-targeted treatments. There is a lack of suitable methods for clinical in vivo HER2 expression assessment. Affibody molecules are small affinity proteins ideal for imaging detection of receptors, which are engineered using a small (molecular weight 6.5 kDa) nonimmunoglobulin scaffold. Labeling of Affibody molecules with positron emitters enabled the development of sensitive and specific agents for molecular imaging. The development of probes for SPECT would permit the use of Affibody-based imaging in regions where PET is not available. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the 99mTc-ZHER2:41071 Affibody molecule developed for SPECT/CT imaging of HER2 expression. Methods: Thirty-one patients with primary breast cancer were enrolled and divided into three cohorts (injected with 500, 1000, or 1500 µg ZHER2:41071) comprising at least five patients with high (positive) HER2 tumor expression (IHC score 3+ or 2+ and ISH positive) and five patients with low (IHC score 2+ or 1+ and ISH negative) or absent HER2 tumor expression. Patients were injected with 451 ± 71 MBq 99mTc-ZHER2:4107. Planar scintigraphy was performed after 2, 4, 6 and 24 h, and SPECT/CT imaging followed planar imaging 2, 4 and 6 h after injection. Results: Injections of 99mTc-ZHER2:41071 were well tolerated and not associated with adverse events. Normal organs with the highest accumulation were the kidney and liver. The effective dose was 0.019 ± 0.004 mSv/MBq. Injection of 1000 µg provided the best standard discrimination between HER2-positive and HER2-low or HER2-negative tumors 2 h after injection (SUVmax 16.9 ± 7.6 vs. 3.6 ± 1.4, p < 0.005). The 99mTc-ZHER2:41071 uptake in HER2-positive lymph node metastases (SUVmax 6.9 ± 2.4, n = 5) was significantly (p < 0.05) higher than that in HER2-low/negative lymph nodes (SUVmax 3.5 ± 1.2, n = 4). 99mTc-ZHER2:41071 visualized hepatic metastases in a patient with liver involvement. Conclusions: Injections of 99mTc-ZHER2:41071 appear safe and exhibit favorable dosimetry. The protein dose of 1000 µg provides the best discrimination between HER2-positive and HER2-low/negative expression of HER2 according to the definition used for current HER2-targeting drugs.
Developing an efficient MGCR microneedle nanovaccine patch for eliciting Th 1 cellular response against the SARS-CoV-2 infection
Authors: Ang Gao, Yunsheng Chen, Hui Liang, Xinyuan Cui, Amin Zhang, Daxiang Cui
Journal: Theranostics (2023)

Rationale: Novel vaccine R&D is essential to interrupt the COVID-19 pandemic and other epidemics in the future. Subunit vaccines have received tremendous attention for their low cost and safety. To improve the immunogenicity of subunit vaccines, we developed a novel vaccine adjuvant system. Methods: Here we rationally designed a CpG 1018 and graphene oxide-based bi-adjuvant system to deliver the Receptor-Binding Domain (RBD) of the SARS-CoV-2 spike protein and obtained the graphene oxide-based complex adjuvant nanovaccine (GCR). Furthermore, we developed a microneedle patch vaccine (MGCR) based on the GCR vaccine. Results: GCR nanovaccine displayed superb antigen loading and encapsulation efficiency. Two dosages of vaccination of GCR nanovaccine could elicit adequate RBD-specific binding antibody response with 2.14-fold higher IgG titer than Alum adjuvant vaccine. The peptide pools assay demonstrated the robust RBD-specific Type 1 Cellular response induced by the GCR nanovaccine in CD8+ T cells. Furthermore, we prepared an MGCR microneedle patch, which generated a similar RBD-specific binding antibody response to the GCR vaccine, sustained a high antibody level above 16 weeks, and significantly elevated the Tcm proportion in mouse spleen. The MGCR microneedle patch vaccine also could be stably stored at room temperature for several months and administrated without medical staff, which maximizes the vaccine distribution efficiency. Conclusion: The vaccine system could significantly improve the vaccine distribution rate in low-income areas and offer a potential vaccination approach to fight against the SARS-Cov-2 infection and other pandemics occurred in the future.
Targeting redox imbalance in neurodegeneration: characterizing the role of GLP-1 receptor agonists
Authors: Puja Ghosh, Rosaria Anna Fontanella, Lucia Scisciola, Ada Pesapane, Fatemeh Taktaz, Martina Franzese, Armando Puocci, Antonio Ceriello, Francesco Prattichizzo, Maria Rosaria Rizzo, Giuseppe Paolisso, Michelangela Barbieri
Journal: Theranostics (2023)

Reactive oxygen species (ROS) have emerged as essential signaling molecules regulating cell survival, death, inflammation, differentiation, growth, and immune response.Environmental factors, genetic factors, or many pathological condition such as diabetes increase the level of ROS generation by elevating the production of advanced glycation end products, reducing free radical scavengers, increasing mitochondrial oxidative stress, and by interfering with DAG-PKC-NADPH oxidase and xanthine oxidase pathways.Oxidative stress, and therefore the accumulation of intracellular ROS, determines the deregulation of several proteins and caspases, damages DNA and RNA, and interferes with normal neuronal function.Furthermore, ROS play an essential role in the polymerization, phosphorylation, and aggregation of tau and amyloid-beta, key mediators of cognitive function decline.At the neuronal level, ROS interfere with the DNA methylation pattern and various apoptotic factors related to cell death, promoting neurodegeneration.Only few drugs are able to quench ROS production in neurons.The cross-linking pathways between diabetes and dementia suggest that antidiabetic medications can potentially treat dementia.Among antidiabetic drugs, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been found to reduce ROS generation and ameliorate mitochondrial function, protein aggregation, neuroinflammation, synaptic plasticity, learning, and memory.The incretin hormone glucagon-like peptide-1 (GLP-1) is produced by the enteroendocrine L cells in the distal intestine after food ingestion.Upon interacting with its receptor (GLP-1R), it regulates blood glucose levels by inducing insulin secretion, inhibiting glucagon production, and slowing gastric emptying.No study has evidenced a specific GLP-1RA pathway that quenches ROS production.Here we summarize the effects of GLP-1RAs against ROS overproduction and discuss the putative efficacy of Exendin-4, Lixisenatide, and Liraglutide in treating dementia by decreasing ROS.